BPI is a 55-Kda protein produced by human neutrophils. Native BPI binds to endotoxins from a variety of gram-negative bacteria and inhibits endotoxin-mediated cellular effects as TNF. Our hypothesis is that BPI given prophylactically or acutely could bolster our natural defenses against toxic bacterial products such as endotoxin resulting in increased neutralization and clearance. Using our canine model in a blinded, controlled, randomized trial with two treatment groups: one receiving 2 mg/kg BPI every 6 h for a total of 3 doses and the other (controls) receiving similar amounts of the vehicle used in the preparation of BPI in a similar manner, we evaluated whether BPI alters survival, bacteremia and endotoxemia. We followed survival, serial hemodynamics, CBCs, blood chemistries, lactate, quantitative blood cultures, TNF and endotoxin levels. Recombinant human BPI, provided by Incyte Pharmaceuticals was used in this experiment. We found that in the dog BPI had a half life of approximately 20 minutes, higher than the usually reported in smaller animals. Unfortunately, in this canine model of septic shock, BPI did not change overall survival, hemodynamics and TNF levels, or bacteremia. However, we found that during the time during which animals were receiving BPI or control therapies, BPI-treated animals had greater survival times compared to controls. A BPI preparation with longer half life is being manufactured. Thus, since early mortality rates were decreased, and endotoxin levels were lowered, we plan to further investigate a longer acting BPI preparation as a potential therapy for sepsis and septic shock.